PROJECT ABSTRACT/SUMMARY Cleft lip with or without cleft palate is the most common congenital malformation of the head and the third most common birth defect. The impact of cleft lip on quality of life for the child and the family can be se- vere, affecting the child's appearance, speech, hearing, growth, psychosocial well-being and social integration. Surgical repair of the lip is the only treatment and is usually performed during the first year of life. However, hypertrophic scar (HTS) formation is a frequent postoperative complication that impairs soft tissue form, func- tion or movement and multiple lip revision surgeries are required throughout childhood for optimum esthetics and function. Uncontrolled and prolonged inflammation plays a major role in tissue injury, tissue scarring, and fibrosis. There is a critical need for new therapeutic regimens to help patients prone to scar tissue formation after lip repair and revision surgeries. The objective of this proposal is to evaluate a new approach to promote wound healing and limit scarring based on endogenous specialized pro-resolving lipid mediators (SPMs), termed Resolvins. The overarching hypothesis is that resolvins applied topically will minimize hypertrophic scarring after cleft lip repair surgery by promoting resolution of inflammation. The problem will be approached in two phases: the actions of resolvins in prevention of lip scarring will be determined in an animal model, fol- lowed by initial human studies that will generate hypotheses for future human clinical application. The specific aims are: 1a) Characterize the inflammatory/lipid mediator profile of hypertrophic scars after cleft lip defect re- pair in an FDA approved animal model; 1b) Using the rabbit model, we will determine the impact of a well characterized specialized pro-resolving lipid mediator (RvE1) on scar formation and inflammatory/lipid media- tors in wound healing after cleft lip defect repair; 2) Characterize the human inflammatory/lipid mediator profile of cleft lip wound exudate and correlate it with scarring in patients undergoing cleft lip repair surgery. These aims also provide a mentored training experience for Dr. Evangelos Papathanasiou, a talented junior dentist-scientist with a strong background in Immunology and Oral Biology. Dr. Papathanasiou's career goal is to integrate advances in drug development, tissue engineering and clinical research in order to develop new bio-engineered approaches for the regeneration of oral and craniofacial tissues and discover novel treat- ments for oral diseases. Dr. Papathanasiou with his mentors, Dr. Carroll Ann Trotman and Dr. Thomas Van Dyke, has assembled a team of highly experienced collaborators with active funded research programs and with commitment to his success, and to ensure an optimal training and research environment and successful outcomes of the proposed research. The expected outcome of this K08 award is to help Dr. Papathanasiou build a strong foundation for a career as an independent scientist in Clinical Translational Dental Research and to lead future human clinical trials of novel endogenous specialized pro-resolving lipid mediators for accelerat- ing wound healing and minimizing fibrosis and scarring.